Devices and methods for frequent measurement of an analyte present in a biological system

ABSTRACT

Devices and methods are provided for frequently measuring the concentration of an analyte present in a biological system. A monitoring system having at least two components is employed in order to allow separation of data collection from data processing and display. Such separation allows greater flexibility and convenience for the user.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.09/503,227, filed 11 Feb. 2000, now U.S. Pat. No. 6,561,978, whichclaims the benefit of U.S. Provisional Application Ser. No. 60/119,918,filed 12 Feb. 1999, now abandoned, all of which applications are hereinincorporated by reference in their entireties.

TECHNICAL FIELD

The present invention is in the field of medical devices. Moreparticularly it relates to methods and devices for measuring an analytepresent in a biological system.

BACKGROUND

Self-monitoring of blood glucose is a critical part of managingdiabetes. However, present procedures for obtaining such information areinvasive, painful and provide only periodic measurements. Standardmethods of measuring involve the use of painful and cumbersome fingerstick blood tests. Thus, development of a painless and automaticapproach would represent a significant improvement in the quality oflife for people with diabetes. Further, a tight glucose control regimen,which uses frequent glucose measurements to guide the administration ofinsulin or oral hypoglycemic agents, leads to a substantial decrease inthe long-term complications of diabetes. See, Diabetes Control andComplication Trial Research Group (1993) N. Engl. J. Med. 329:997–1036.

SUMMARY OF THE INVENTION

In one aspect, the invention includes a monitoring system for frequentlymeasuring an analyte present in a biological system, said monitoringsystem comprising,

(a) a first component comprising

-   -   (i) a transdermal or transmucosal sampling mechanism for        extracting the analyte from the biological system, wherein said        sampling mechanism is adapted for extracting the analyte across        a skin or mucosal surface of said biological system;    -   (ii) sensing mechanism in operative contact with the analyte        extracted by the sampling mechanism, wherein said sensing        mechanism obtains a signal from the extracted analyte and said        signal is specifically related to the analyte; and    -   (iii) first mechanism for providing operative communication with        a second component of the monitoring system; and

(b) a second component comprising

-   -   (i) a user interface; and    -   (ii) second mechanism for providing operative communication with        the first component.

In certain embodiments, the sampling mechanism is iontophoresis,electroosmosis, sonophoresis, microdialysis, suction and passivediffusion. In certain embodiments, the first component further comprisesa computing mechanism that converts the signal from the extractedanalyte to an output indicative of the amount of analyte extracted bythe sampling mechanism. The output can be communicated to the secondcomponent for display. Further, in other embodiments, the secondcomponent receives the signal from the first component, wherein thesecond component further comprises a computing mechanism that convertsthe signal from the extracted analyte to an output indicative of theamount of analyte extracted by the sampling mechanism and wherein thesecond component displays said output. The first and second mechanismsfor providing operative communication can comprise a wire-likeconnection, wireless communication technology or a combination ofwire-like and wireless technologies. Wireless communication technologycan employ, for example electromagnetic waves (e.g, low frequencyelectromagnetic waves in a frequency range of about 1 Hz. to about 1Mega Hz; medium frequency electromagnetic waves in a frequency range ofabout 1 Mega Hz. to about 500 Mega Hz or high frequency electromagneticwaves in a frequency range of about 500 Mega Hz. to about 5 Giga Hz);capacitance coupling between the biological system and the biologicalsystem's environment; inductive coupling; infrared coupling; highfrequency acoustic energy or combinations thereof. In still furtherembodiments, the second component of the monitoring system relayscommand signals to the first component, for example, signals to controloperation of the sensing mechanism or signals to control operation ofthe sampling mechanism. In certain embodiments, the second component canstore analyte-related data. In yet another embodiments, the analyte isglucose. In certain embodiments, the biological system is a mammal, forexample a human.

In yet another aspect of the invention, the monitoring system asdescribed herein that further comprises

-   -   (c) a third component comprising        -   (i) a delivery device; and        -   (ii) a third mechanism for providing operative communication            with the first and second components. The delivery device            can be implanted in the biological system (e.g.,            subcutaneously) or, alternatively, can be external to the            biological system. In certain embodiments, the analyte is            glucose and the delivery device comprises an insulin pump.            In certain embodiments, the communication between first and            second components and the third component is wireless, for            example, one or more of the wireless technologies described            herein.

In yet another aspect, the invention includes a monitoring systemdescribed herein that further comprises

-   -   (c) a third component comprising        -   (i) a modem or personal computer; and        -   (ii) a third mechanism for providing operative communication            with the first and second components. In certain            embodiments, the modem or personal computer is remote from            the biological system and the communication between the            first and second components and the third component is            wireless. The modem or personal computer may also be            operably linked to a wide area network (WAN), for example            the internet. In certain embodiments, the analyte is            glucose.

These and other embodiments of the present invention will readily occurto those of ordinary skill in the art in view of the disclosure herein.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A to 1L show representative embodiments of a monitoring system ofthe present invention which has two components. FIGS. 1A through 1Hdepict a two component system while FIGS. 1I through 1L depict a systemhaving three components.

DETAILED DESCRIPTION OF THE INVENTION

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particular formulationsor process parameters, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments of the invention only, and is notintended to be limiting.

The present invention relates to monitoring systems generally used forextracting small amounts of a target analyte from the biological system,and then sensing and/or quantifying the concentration of the targetanalyte. Unlike previous devices, the sampling/sensing mechanism anduser interface are found on separate components. Thus, the presentinvention relates to a monitoring system with at least two components,in which a first component comprises sampling mechanism and sensingmechanism that are used to extract and detect an analyte, for example,glucose, and a second component that receives the analyte data from thefirst component, conducts data processing on the analyte data todetermine an analyte concentration and then displays the analyteconcentration data. Typically, microprocessor functions (e.g., controlof sampling/sensing, different aspects of data manipulation orrecording) are found in both components. Alternatively, microprocessingcomponents may be located in one or the other of the at least twocomponents. The second component of the monitoring system can assumemany forms, including, but not limited to, the following: a watch, acredit card-shaped device (e.g., a “smart card” or “universal card”having a built-in microprocessor as described for example in U.S. Pat.No. 5,892,661), a pager-like device, cell phone-like device, or othersuch device that communicates information to the user visually, audibly,or kinesthetically.

Further, additional components may be added to the system, for example,a third component comprising a display of analyte values or an alarmrelated to analyte concentration, may be employed. In certainembodiments, an insulin delivery unit (e.g., insulin pump) is includedin the system. Insulin delivery units, both implantable and external,are known in the art and described, for example, in U.S. Pat. Nos.5,995,860; 5,112,614 and 5,062,841. Preferably, when included as acomponent of the present invention, the insulin delivery unit is incommunication (e.g., wire-like or wireless communication) with theextracting and/or sensing mechanism such that the sensing mechanism cancontrol the insulin pump and regulate delivery of a suitable amount ofinsulin to the subject.

Advantages of separating the first component (e.g., including thebiosensor and iontophoresis functions) from the second component (e.g.,including some microprocessor and display functions) include greaterflexibility, discretion, privacy and convenience to the user. Having asmall and lightweight measurement unit allows placement of the twocomponents of the system on a wider range of body sites, for example,the first component may be placed on the abdomen or upper arm. Thiswider range of placement options may improve the accuracy throughoptimal extraction site selection (e.g., torso rather than extremities)and greater temperature stability (e.g., via the insulating effects ofclothing). Thus, the collection and sensing assembly will be able to beplaced on a greater range of body sites. Similarly, a smaller and lessobtrusive microprocessor and display unit (the second component)provides a convenient and discrete system by which to monitor analytes.The biosensor readouts and control signals will be relayed via wire-likeor wireless technology between the collection and sensing assembly andthe display unit which could take the form of a small watch, a pager, ora credit card-sized device. This system also provides the ability torelay an alert message or signal during nighttime use, for example, to asite remote from the subject being monitored.

In one embodiment, the two components of the device can be in operativecommunication via a wire or cable-like connection. In preferredembodiments, the mechanism for providing operative communication betweenthe two components is wireless. FIGS. 1A to 1H show exemplaryembodiments of monitoring systems having two components. FIGS. 1I to 1Lshow exemplary embodiments of monitoring systems having threecomponents. These exemplary embodiments are described in further detailbelow.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.

I. Definitions

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a”, “an” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to “a binder” includes a mixture of two or more such binders,reference to “an analyte” includes mixtures of analytes, and the like.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice for testing of the present invention, the preferredmaterials and methods are described herein. In describing and claimingthe present invention, the following terminology will be used inaccordance with the definitions set out below.

The terms “analyte” and “target analyte” are used herein to denote anyphysiological analyte of interest that is a specific substance orcomponent that is being detected and/or measured in a chemical,physical, enzymatic, or optical analysis. A detectable signal (e.g., achemical signal or electrochemical signal) can be obtained, eitherdirectly or indirectly, from such an analyte or derivatives thereof.Furthermore, the terms “analyte” and “substance” are usedinterchangeably herein, and are intended to have the same meaning, andthus encompass any substance of interest. In preferred embodiments, theanalyte is a physiological analyte of interest, for example, glucose, ora chemical that has a physiological action, for example, a drug orpharmacological agent.

A “sampling device,” “sampling mechanism” or “sampling system” refers toany device for obtaining a sample from a biological system for thepurpose of determining the concentration of an analyte of interest. Such“biological systems” include any biological system from which theanalyte of interest can be extracted, including, but not limited to,blood, interstitial fluid, perspiration and tears. Further, a“biological system” includes both living and artificially maintainedsystems. As used herein, the term “sampling” mechanism refers toextraction of a substance from the biological system, generally across amembrane such as skin or mucosa. The membrane can be natural orartificial, and can be of plant or animal nature, such as natural orartificial skin, blood vessel tissue, intestinal tissue, and the like.Typically, the sampling mechanism are in operative contact with a“reservoir,” or “collection reservoir,” wherein the sampling mechanismis used for extracting the analyte from the biological system into thereservoir to obtain the analyte in the reservoir. Non-limiting examplesof sampling techniques include iontophoresis, sonophoresis, suction,electroporation, thermal poration, passive diffusion, microfine(miniature) lances or cannulas, subcutaneous implants or insertions, andlaser devices. Iontophoretic sampling devices are described, forexample, in International Publication No. WO 97/24059, published Jul.10, 1997; European Patent Application EP 0942 278, published 15 Sep.1999; International Publication No. WO 96/00110, published 4 Jan. 1996;International Publication No. WO 97/10499, published 2 Mar. 1997; U.S.Pat. Nos. 5,279,543; 5,362,307; 5,730,714; 5,771,890; 5,989,409;5,735,273; 5,827,183; 5,954,685 and 6,023,629, all of which are hereinincorporated by reference in their entireties. Sonophoresis usesultrasound to increase the permeability of the skin (see, e.g., Menon etal. (1994) Skin Pharmacology 7:130–139). An exemplary sonophoresissampling system is described in International Publication No. WO91/12772, published 5 Sep. 1991. Passive diffusion sampling devices aredescribed, for example, in International Publication Nos.: WO 97/38126(published 16 Oct. 1997); WO 97/42888, WO 97/42886, WO 97/42885, and WO97/42882 (all published 20 Nov. 1997); and WO 97/43962 (published 27Nov. 1997). Laser devices use a small laser beam to create one or moremicropores in the uppermost layer of the patient's skin (see, e.g.,Jacques et al. (1978) J. Invest. Dermatology 88:88–93; InternationalPublication WO 99/44507, published, Sep. 10, 1999; InternationalPublication WO 99/44638, published, Sep. 10, 1999; and InternationalPublication WO 99/40848, published, Aug. 19, 1999.

The term “collection reservoir” is used to describe any suitablecontainment mechanism for containing a sample extracted from abiological system. For example, the collection reservoir can be areceptacle containing a material which is ionically conductive (e.g.,water with ions therein), or alternatively, it can be a material, suchas, a sponge-like material or hydrophilic polymer, used to keep thewater in place or to contain the water. Such collection reservoirs canbe in the form of a hydrogel (for example, in the form of a disk orpad). Hydrogels are typically referred to as “collection inserts.” Othersuitable collection reservoirs include, but are not limited to, tubes,vials, capillary collection devices, cannulas, and miniaturized etched,ablated or molded flow paths.

A “housing” for the sampling system can include suitable electronics(e.g., microprocessor, memory, display and other circuit components) andpower sources for operating the sampling system in an automatic fashion.

A “monitoring system,” as used herein, refers to a system useful forfrequently measuring a physiological analyte present in a biologicalsystem. Such a system typically includes, but is not limited to,sampling mechanism, sensing mechanism, and a microprocessor mechanism inoperative communication with the sampling mechanism and the sensingmechanism. As used herein, the term “frequent measurement” intends aseries of two or more measurements obtained from a particular biologicalsystem, which measurements are obtained using a single device maintainedin operative contact with the biological system over the time period(e.g. second, minute or hour intervals) in which the series ofmeasurements is obtained. The term thus includes continual andcontinuous measurements.

The term “subject” encompasses any warm-blooded animal, particularlyincluding a member of the class Mammalia such as, without limitation,humans and nonhuman primates such as chimpanzees and other apes andmonkey species; farm animals such as cattle, sheep, pigs, goats andhorses; domestic mammals such as dogs and cats; laboratory animalsincluding rodents such as mice, rats and guinea pigs, and the like. Theterm does not denote a particular age or sex. Thus, adult and newbornsubjects, whether male or female, are intended to be covered.

The term “transdermal,” as used herein, includes both transdermal andtransmucosal techniques, i.e., extraction of a target analyte acrossskin or mucosal tissue. Aspects of the invention which are describedherein in the context of “transdermal,” unless otherwise specified, aremeant to apply to both transdermal and transmucosal techniques.

The term “transdermal extraction,” or “transdermally extracted” intendsany sampling method, which entails extracting and/or transporting ananalyte from beneath a tissue surface across skin or mucosal tissue. Theterm thus includes extraction of an analyte using iontophoresis (reverseiontophoresis), electroosmosis, sonophoresis (see, e.g., U.S. Pat. No.5,636,632), microdialysis, suction, and passive diffusion. These methodscan, of course, be coupled with application of skin penetrationenhancers or skin permeability enhancing technique such as varioussubstances or physical methods such as tape stripping or pricking withmicro-needles. The term “transdermally extracted” also encompassesextraction techniques which employ thermal poration, lasermicroporation, electroporation, microfine lances, microfine canulas,subcutaneous implants or insertions, and the like.

The term “iontophoresis” intends a method for transporting substancesacross tissue by way of an application of electrical energy to thetissue. In conventional iontophoresis, a reservoir is provided at thetissue surface to serve as a container of material to be transported.Iontophoresis can be carried out using standard methods known to thoseof skill in the art, for example, by establishing an electricalpotential using a direct current (DC) between fixed anode and cathode“iontophoretic electrodes,” alternating a direct current between anodeand cathode iontophoretic electrodes, or using a more complex waveformsuch as applying a current with alternating polarity (AP) betweeniontophoretic electrodes (so that each electrode is alternately an anodeor a cathode), as described for example in U.S. Pat. Nos. 5,771,890 and6,023,629.

The term “reverse iontophoresis” refers to the movement of a substancefrom a biological fluid across a membrane by way of an applied electricpotential or current. In reverse iontophoresis, a reservoir is providedat the tissue surface to receive the extracted material, as used in theGluco Watch® (Cygnus, Inc., Redwood City, Calif.) glucose monitor (See,e.g., Tanada et al. (1999) JAMA 282:1839–1844).

“Electroosmosis” refers to the movement of a substance through amembrane by way of an electric field-induced convective flow. The termsiontophoresis, reverse iontophoresis, and electroosmosis, will be usedinterchangeably herein to refer to movement of any ionically charged oruncharged substance across a membrane (e.g., an epithelial membrane)upon application of an electric potential to the membrane through anionically conductive medium.

The term “sensing device,” “sensing mechanism,” or “biosensor device”encompasses any device that can be used to measure the concentration ofan analyte, or derivative thereof, of interest. Preferred sensingdevices for detecting blood analytes generally include electrochemicaldevices, optical and chemical devices and combinations thereof. Examplesof electrochemical devices include the Clark electrode system (see,e.g., Updike, et al., (1967) Nature 214:986–988), and otheramperometric, coulometric, or potentiometric electrochemical devices.Examples of optical devices include conventional enzyme-based reactionsas used in the Lifescan® (Johnson and Johnson, New Brunswick, N.J.)glucose monitor (see, e.g., U.S. Pat. No. 4,935,346 to Phillips, etal.).

A “biosensor” or “biosensor device” includes, but is not limited to, a“sensor element” which includes, but is not limited to, a “biosensorelectrode” or “sensing electrode” or “working electrode” which refers tothe electrode that is monitored to determine the amount of electricalsignal at a point in time or over a given time period, which signal isthen correlated with the concentration of a chemical compound. Thesensing electrode comprises a reactive surface which converts theanalyte, or a derivative thereof, to electrical signal. The reactivesurface can be comprised of any electrically conductive material suchas, but not limited to, platinum-group metals (including, platinum,palladium, rhodium, ruthenium, osmium, and iridium), nickel, copper,silver, and carbon, as well as, oxides, dioxides, combinations or alloysthereof. Some catalytic materials, membranes, and fabricationtechnologies suitable for the construction of amperometric biosensorsare described by Newman, J. D., et al.(1995) Analytical Chemistry67:4594–4599.

The “sensor element” can include components in addition to a biosensorelectrode, for example, it can include a “reference electrode,” and a“counter electrode.” The term “reference electrode” is used herein tomean an electrode that provides a reference potential, e.g., a potentialcan be established between a reference electrode and a workingelectrode. The term “counter electrode” is used herein to mean anelectrode in an electrochemical circuit which acts as a current sourceor sink to complete the electrochemical circuit. Although it is notessential that a counter electrode be employed where a referenceelectrode is included in the circuit and the electrode is capable ofperforming the function of a counter electrode, it is preferred to haveseparate counter and reference electrodes because the referencepotential provided by the reference electrode is most stable when it isat equilibrium. If the reference electrode is required to act further asa counter electrode, the current flowing through the reference electrodemay disturb this equilibrium. Consequently, separate electrodesfunctioning as counter and reference electrodes are most preferred.

In one embodiment, the “counter electrode” of the “sensor element”comprises a “bimodal electrode.” The term “bimodal electrode” as usedherein typically refers to an electrode which is capable of functioningnon-simultaneously as, for example, both the counter electrode (of the“sensor element”) and the iontophoretic electrode (of the “samplingmechanism”) as described, for example, U.S. Pat. No. 5,954,685.

The terms “reactive surface,” and “reactive face” are usedinterchangeably herein to mean the surface of the sensing electrodethat: (1) is in contact with the surface of an electrolyte containingmaterial (e.g. gel) which contains an analyte or through which ananalyte, or a derivative thereof, flows from a source thereof; (2) iscomprised of a catalytic material (e.g., carbon, platinum, palladium,rhodium, ruthenium, or nickel and/or oxides, dioxides and combinationsor alloys thereof) or a material that provides sites for electrochemicalreaction; (3) converts a chemical signal (e.g. hydrogen peroxide) intoan electrical signal (e.g., an electrical current); and (4) defines theelectrode surface area that, when composed of a reactive material, issufficient to drive the electrochemical reaction at a rate sufficient togenerate a detectable, reproducibly measurable, electrical signal thatis correlatable with the amount of analyte present in the electrolyte.

An “ionically conductive material” refers to any material that providesionic conductivity, and through which electrochemically active speciescan diffuse. The ionically conductive material can be, for example, asolid, liquid, or semi-solid (e.g., in the form of a gel) material thatcontains an electrolyte, which can be composed primarily of water andions (e.g., sodium chloride), and generally comprises 50% or more waterby weight. The material can be in the form of a gel, a sponge or pad(e.g., soaked with an electrolytic solution), or any other material thatcan contain an electrolyte and allow passage therethrough ofelectrochemically active species, especially the analyte of interest.

The term “physiological effect” encompasses effects produced in thesubject that achieve the intended purpose of a therapy. In preferredembodiments, a physiological effect mechanism that the symptoms of thesubject being treated are prevented or alleviated. For example, aphysiological effect would be one that results in the prolongation ofsurvival in a patient.

The terms “collection assembly,” as used herein, refers to any structurethat can be used to collect the analyte of interest. Similarly, an“autosensor assembly” refers to any structure capable of sensing theanalyte of interest. The structures may be comprised of several layers,for example, a collection reservoir, a mask layer, liners and/or aretaining layer where the layers are held in appropriate, functionalrelationship to each other. The autosensor assembly may also includeliners. Exemplary collection assemblies and autosensor structures aredescribed, for example, in International Publication WO 99/58190,published 18 Nov. 1999; and U.S. Pat. Nos. 5,735,273 and 5,827,183.

“Substantially planar” as used herein, includes a planar surface thatcontacts a slightly curved surface, for example, a forearm or upper armof a subject. A “substantially planar” surface is, for example, asurface having a shape to which skin can conform, i.e., contactingbetween the skin and the surface.

By the term “printed” as used herein is meant a substantially uniformdeposition of an electrode formulation onto one surface of a substrate(i.e., the base support). It will be appreciated by those skilled in theart that a variety of techniques may be used to effect substantiallyuniform deposition of a material onto a substrate, e.g., Gravure-typeprinting, extrusion coating, screen coating, spraying, painting, or thelike.

The term “user interface” refers to any means or mechanism thatinteracts (e.g., provides or exchanges information) with any one of auser's senses. Non-limiting examples of suitable interfaces includevisual displays (e.g., LCD displays); tactile or mechanical signals(e.g., vibrations, alarms, buttons, etc.) and auditory signals (e.g.,alarm or speaker). The term “microprocessor” refers to any type ofdevice that functions as a microcontroller and also includes any type ofprogrammable logic, for example, Flexible Program Gate Array (FPGA).

As used herein, the term “wire-like” refers to communications involvingthe transport of signals from one location to another using a wire,cable or other solid object. Examples include the transport of electriccharge and/or voltage on metallic wires and the transport of lightenergy on fiber optic cables. The term “wireless” refers tocommunications involving the transport of signals from one location toanother without the use of wires or cables. Examples include, but arenot limited to: the transport of signals through space viaelectromagnetic waves; the transport of signals through air via pressurewaves (e.g., acoustic signals); the transport of signals through spacevia magnetic fields; the transport of signals through space via electricfields; and combinations of one or more of the foregoing. The term“transceiver” refers to any device which is capable of functioning asboth a transmitter and a receiver of signals. An integrated transceiversystem is described, for example, in U.S. Pat. No. 5,930,686.

II. General Overview

The present invention is based on the novel concept of separating ananalyte monitoring system into at least two components. The firstcomponent samples (extracts) and senses (detects) the analyte ofinterest while the second component includes a user interface. Dataprocessing on the analyte data can be performed by the first component,the second component or both. Additional components, for example, analarm or a drug delivery unit, can also be included. Particularcomponents of the subject invention are described below. It is to beunderstood that the various forms of different embodiments of theinvention may be combined.

Thus, the present invention relates to a monitoring system, forfrequently measuring an analyte present in a biological system,comprising a measurement unit (e.g., sampling mechanism and sensingmechanism) in operative communication with a second component (e.g., auser interface). Further components can be included in the system aswell, for example, a third component having display mechanism (displayunit), a delivery unit and/or electronic file data serving mechanism.Providing such a system in at least two parts imparts greaterflexibility and convenience to the user. In one embodiment, thecommunication connection between the components can be a wire-likeconnection (e.g., a wire or multi-wire cable). In a preferredembodiment, operative communications between the components is awireless link, i.e. provided by a “virtual cable,” for example, atelemetry link. This wireless link can be uni- or bi-directional betweenthe two components. In the case of more than two components, links canbe a combination of wire-like and wireless.

This monitoring system comprising at least two components relaysbiosensor information from the measurement unit to the user interfacefor subsequent analysis and display. It can also relay command signalsand information from the user interface to the measurement unit in orderto control sensing (e.g., the biosensor) and sampling (e.g.,iontophoresis) functions; data processing (e.g., calibration values);and event logging (e.g., meals, exercise, etc.). In some embodiments,additional components, for example, an insulin delivery unit can beincluded. The insulin delivery unit can receive commands from themeasuring system and deliver suitable amounts of insulin.

III. Sampling Mechanism and Sensing Mechanism

The monitoring system of the present invention comprises at least twocomponents, as shown for example in the Figures. The first componenttypically includes both sampling and sensing mechanism and, optionally,a power source and a controller (microprocessor). In one aspect, thesampling/sensing mechanism is placed on the skin, e.g., for example fortransdermal or transmucosal sampling/sensing. Alternatively, one or moreaspects of the sampling/sensing mechanisms can be implanted, forexample, subcutaneously into a user. In a preferred embodiment, thesampling mechanism can comprise sampling (e.g., iontophoretic)electrodes that are used to perform frequent transdermal or transmucosalsampling of an analyte of interest (e.g., glucose). The sensingmechanism can comprise biosensor electrodes (see, e.g., European PatentApplication EP 0942 278, published 15 Sep. 1999). The sensing mechanismis typically in operative contact with the extracted analyte and obtainsa signal from the extracted analyte. The signal is specifically relatedto the analyte. Thus, the first component provides the mechanism tosample and sense the presence of an analyte, for example by detectingelectrochemical signals produced at the biosensor electrode surfaces.Consumable collection assemblies that provide sampling and sensingfunctions are described, for example in International Publication WO99/58190, published 18 Nov. 1999.

A. Analytes

The analyte to be monitored by the invention described herein can be anyspecific substance or component that one is desirous of detecting and/ormeasuring in a chemical, physical, enzymatic, or optical analysis. Suchanalytes include, but are not limited to, amino acids, enzyme substratesor products indicating a disease state or condition, other markers ofdisease states or conditions, drugs of abuse, therapeutic and/orpharmacologic agents (e.g., theophylline, anti-HIV drugs, lithium,anti-epileptic drugs, cyclosporin, chemotherapeutics), electrolytes,physiological analytes of interest (e.g., urate/uric acid, carbonate,calcium, potassium, sodium, chloride, bicarbonate (CO₂), glucose, urea(blood urea nitrogen), lactate/lactic acid, hydroxybutyrate,cholesterol, triglycerides, creatine, creatinine, insulin, hematocrit,and hemoglobin), blood gases (carbon dioxide, oxygen, pH), lipids, heavymetals (e.g., lead, copper), and the like. In preferred embodiments, theanalyte is a physiological analyte of interest, for example glucose, ora chemical that has a physiological action, for example a drug orpharmacological agent.

In one embodiment, the analyte is detected by specific enzyme systems.For example, in the case of glucose, the enzyme glucose oxidasecatalyzes a redox reaction which produces hydrogen peroxide from glucoseand oxygen. A number of other analyte-specific enzyme systems can beused in the invention, which enzyme systems operate on much the samegeneral techniques. For example, a biosensor electrode that detectshydrogen peroxide can be used to detect ethanol using an alcohol oxidaseenzyme system, or similarly uric acid with urate oxidase system,cholesterol with a cholesterol oxidase system, and theophylline with axanthine oxidase system.

In addition, the oxidase enzyme (used for hydrogen peroxidase-baseddetection) can be replaced with another redox system, for example, thedehydrogenase-enzyme NAD-NADH, which offers a separate route todetecting additional analytes. Dehydrogenase-based sensors can useworking electrodes made of gold or carbon (via mediated chemistry).Examples of analytes suitable for this type of monitoring include, butare not limited to, cholesterol, ethanol, hydroxybutyrate, phenylalanineand triglycerides. Further, the enzyme can be eliminated and detectioncan rely on direct electrochemical or potentiometric detection of ananalyte. Such analytes include, without limitation, heavy metals (e.g.,cobalt, iron, lead, nickel, zinc), oxygen, carbonate/carbon dioxide,chloride, fluoride, lithium, pH, potassium, sodium, and urea. Also, thesampling system described herein can be used for therapeutic drugmonitoring, for example, monitoring anti-epileptic drugs (e.g.,phenytion), chemotherapy (e.g., adriamycin), hyperactivity (e.g.,ritalin), and anti-organ-rejection (e.g., cyclosporin).

Appropriate formulations of analyte test solutions can be employed andare readily determined by one of skill in the art. For example, testsolutions having known concentrations of alcohol, uric acid,cholesterol, or theophylline may be used herein. The solutions maycontain additives, diluents, solubilizers, and the like, that do notinterfere with detection of the analyte of interest by the samplingsystem.

Therefore, it is to be understood that, although discussed primary withrespect to glucose herein, the present invention is also applicable tothe monitoring of other analytes of interest.

B. Sampling Mechanism

Typically, the sampling mechanism is based on transdermal extraction.Measurement and/or sampling with the monitoring system can be carriedout in a frequent manner. Frequent measurements allow for closermonitoring of target analyte concentration fluctuations. Morespecifically, an analyte monitoring system is used to measure changes inanalyte levels in an animal subject over a wide range of analyteconcentrations. The device can be contacted with the biological systemfor extended periods of time, and automatically obtains frequent glucosesamples in order to measure glucose concentration at various selectedintervals.

Sampling is carried out by extracting an analyte (e.g., glucose) throughthe skin of the patient. It is to be understood that extraction of theanalyte can be conducted using a variety of methods, for example,iontophoresis, sonophoresis, suction, electroporation, thermal poration,passive diffusion, microfine (miniature) lances or cannulas,subcutaneous implants or insertions, laser devices and other methodsknown to those of skill in the art. In one aspect, an iontophoreticcurrent is applied to a surface of the skin of a subject. When thecurrent is applied, ions or charged molecules pull along other unchargedmolecules or particles such as glucose which are drawn into a collectionreservoir placed on the surface of the skin. The collection reservoirmay comprise any ionically conductive material and is preferably in theform of a hydrogel which is comprised of a hydrophilic material, waterand an electrolyte.

In one aspect, the sampling device can operate in an alternatingpolarity mode necessitating the presence of first and second bimodalelectrodes and two collection reservoirs. Each bi-modal electrode servestwo functions depending on the phase of the operation: (1) anelectro-osmotic electrode (or iontophoretic electrode) used toelectrically draw analyte from a source into a collection reservoircomprising water and an electrolyte, and to the area of the electrodesubassembly; and (2) as a counter electrode to the first sensingelectrode (described below) at which the chemical compound iscatalytically converted at the face of the sensing electrode to producean electrical signal. Alternating polarity is described, for example, inU.S. Pat. No. 5,954,685.

The iontophoresis (e.g., bi-modal) electrode is preferably comprised ofAg/AgCl, described for example in U.S. Pat. No. 5,954,685 andInternational Publication WO 99/58190. Preferably, the electrodes areformulated using analytical- or electronic-grade reagents and solventsand are provided such that they are not susceptible to attack (e.g.,plasticization) by components in the surrounding environment. Theelectrochemical reaction which occurs at the surface of this electrodeserves as a facile source or sink for electrical current. With regard tooperation for extended periods of time, Ag/AgCl electrodes known in theart are capable of repeatedly forming a reversible couple which operateswithout unwanted electrochemical side reactions (which may give rise tochanges in pH, and liberation of hydrogen and oxygen due to waterhydrolysis).

C. Sensing Mechanism

As noted above, a sensing mechanism for sensing the analyte of interestis also included in the present invention, and can be, for example,based on electrochemical detection techniques. The sensing mechanismobtains a signal from the extracted analyte that is specifically relatedto that analyte. A variety of sensing mechanism find use in the presentinvention, for example, in the case of the analyte glucose, thecollection reservoir may further contain an enzyme which catalyzes areaction of glucose to form an easily detectable species. The enzyme ispreferably glucose oxidase (GOx) which catalyzes the reaction betweenglucose and oxygen and results in the production of hydrogen peroxide.The hydrogen peroxide reacts at a catalytic surface of a biosensorelectrode, resulting in the generation of electrons which create adetectable biosensor current (raw signal).

Suitable biosensor electrodes are described, for example, in EP 0 942278. In brief, the biosensor electrodes are constructed of any suitablematerial, for example, platinum and graphite. The sensor element canalso include a reference electrode, and a counter electrode, a masklayer; a retaining layer and/or one or more liners. Suitableconfigurations (e.g., flexibility, shape, degree of sealing, degree ofisolation of components, degree of occlusivity, adhesion to targetsurface and/or electrodes) can be readily determined by the skilledartisan in view of the teachings herein and devices known in the art,for example as described in EP 0 942 278 and WO 99/58190.

In addition, it may be desirable to configure the sampling/sensingmechanisms (or employ measurement techniques) in such a way that theeffect of interfering species on the sensor is reduced. As described forexample in International Publication WO 99/58051, published 18, Nov.1999, extraction and sensing of the analyte may be conducted using ameasurement sample which selectively favors analyte-specific signalcomponents over signal components due to interfering species, forexample by (a) employing a differential signal process which subtractsnon-analyte signal components from the analyte signal; (b) employing adelay step which is performed between the sampling (extraction) andsensing steps; (c) employing a selective electrochemical detectionprocess performed during the sensing step; (d) employing a purge step,performed after the sensing step; (e) employing a charge segregationstep or (f) any combination of (a) through (e).

The sampling and sensing mechanisms can be combined into one structure.For example, once formulated, the sampling and/or sensing electrodecompositions may be affixed to a suitable rigid or flexiblenonconductive surface. For example, a silver (Ag) underlayer is firstapplied to the surface in order to provide uniform conduction. TheAg/AgCl electrode composition is then applied over the Ag underlayer inany suitable pattern or geometry using various thin film techniques,such as sputtering, evaporation, vapor phase deposition, or the like, orusing various thick film techniques, such as film laminating,electroplating, or the like. Alternatively, the Ag/AgCl composition canbe applied using screen printing, pad printing, inkjet methods, transferroll printing, or similar techniques. (See, e.g., WO 99/58190).

The general operation of an iontophoretic sampling and sensing system isthe cyclical repetition of two phases: (1) a reverse-iontophoreticphase, followed by a (2) sensing phase. During the reverse iontophoreticphase, the first bimodal electrode acts as an iontophoretic cathode andthe second bimodal electrode acts as an iontophoretic anode to completethe circuit. Analyte (e.g., glucose) is collected in the reservoirs, forexample, a hydrogel. At the end of the reverse iontophoretic phase, theiontophoretic current is turned off. During the sensing phase, in thecase of glucose, a potential is applied between the reference electrodeand the sensing electrode. The chemical signal reacts catalytically onthe catalytic face of the first sensing electrode producing anelectrical current, while the first bi-modal electrode acts as a counterelectrode to complete the electrical circuit.

The reference and sensing electrodes, as well as, the bimodal electrodedescribed above are typically connected to a standard potentiostatcircuit during sensing. The electrode sub-assembly can be operated byelectrically connecting the bimodal electrodes such that each electrodeis capable of functioning as both an iontophoretic electrode and counterelectrode along with appropriate sensing electrode(s) and referenceelectrode(s), to create standard potentiostat circuitry.

A potentiostat is an electrical circuit used in electrochemicalmeasurements in three electrode electrochemical cells. A potential isapplied between the reference electrode and the sensing electrode. Thecurrent generated at the sensing electrode flows through circuitry tothe counter electrode (i.e., no current flows through the referenceelectrode to alter its equilibrium potential). Two independentpotentiostat circuits can be used to operate the two biosensors. For thepurpose of the present system, the electrical current measured at thesensing electrode subassembly is the current that is correlated with anamount of chemical signal.

D. Power Source

A power source (e.g., one or more rechargeable and/or nonrechargeablebatteries) can be disposed within the first and/or second components ofthe monitoring system. For example, in embodiments involvingiontophoresis, the power source provides sufficient power to apply anelectric potential (either direct current or a more complex waveform)between the two iontophoretic (sampling) electrodes such that currentflows from the first iontophoretic electrode, through the firstconductive medium into the skin or mucosal surface, and then back outthrough the second conductive medium to the second iontophoreticelectrode. The current flow is sufficient to extract substancesincluding an analyte of interest through the skin into one or both ofthe collection reservoirs. The electric potential may be applied usingany suitable technique, for example, the applied current density may bein the range of about 0.01 to 0.5 mA/cm².

Similarly, during the reverse iontophoretic phase, the power sourceprovides a current flow to the first bi-modal electrode to facilitatethe extraction of the chemical signal into the reservoir. During thesensing phase, the power source is used to provide voltage to the firstsensing electrode to drive the conversion of chemical signals retainedin the reservoir to electrical signals at the catalytic face of thesensing electrode. The power source also maintains a fixed potential atthe electrode where, for example, hydrogen peroxide is converted tomolecular oxygen, hydrogen ions, and electrons, which is compared withthe potential of the reference electrode during the sensing phase. Whileone sensing electrode is operating in the sensing mode it iselectrically connected to the adjacent bimodal electrode which acts as acounter electrode at which electrons generated at the sensing electrodeare consumed.

Non-limiting examples of suitable sources of power include printedbatteries, film batteries, moldable batteries, coin cell batteries,prismatic batteries, or cylindrical batteries. Printed batteries can beincorporated into the monitoring system, for instance in the firstcomponent during printing of the biosensor. In a representativeembodiment, the biosensor is printed onto a 0.005 inch thick PET filmsubstrate. The printed battery can be deposited onto this same substrateusing similar thick-film print processes. Anode, insulator material,electrolyte, cathode and encapsulant material can be deposited insequential steps to create the battery. Electrode materials can bedeposited in charged states, such as by charging a printing screenduring deposition of the electrode layers, thereby avoiding the need tocharge the battery after deposition. Alternatively, film batteries canbe assembled with the other components of the sampling/sensing deviceusing, for example, Solid State System™ lithium-ion solid polymerrechargeable batteries from Ultralife Batteries Inc., Newark, N.Y. Thinfilm batteries and moldable batteries from solid electrodes and/or solidelectrolytes can also be used, such as the “RHISS” technology from ECRCorporation, Rehovot, Israel. Coin-cell, prismatic, or cylindricalbatteries, for example using nickel metal hydride, various lithium,alkaline, zinc-air, chemistries, may also be used and are commerciallyavailable, for example from Panaxonic Industrial, Secaucus, N.J., VartaBatteries Inc., Elmsford, N.Y. It is to be understood that these andother power sources can also be incorporated into the second componentto provide the necessary power to run the user interface and/ormicroprocessing functions contained in the second component. Thus,selection and implementation of a suitable power source can be readilydetermined by one of skill in the art in view of one or more of thefollowing factors: the method of extraction (sampling), for example,iontophoresis, sonophoresis, etc.; the nature of the user interface; themethod of sensing, for example, with biosensor electrodes;manufacturability; energy density; energy capacity; cost; charging time;self-discharging characteristics; environmental concerns; governmentregulations; safety; and user preference.

III. User Interface

The second component of the at least two component monitoring systemcomprises a user interface and, typically, one or more controller(microprocessor) functions. Additional components such as suitableelectronics (e.g., microprocessing, memory, display and other circuitcomponents), a power source, an alarm and the like can also be includedin the user interface. The user interface may provide numericalreadouts, other visual indication of analyte concentration (e.g.,arrows), or visual instruction actions (e.g., take medication, eat ordrink). Buttons on the user interface may provide the ability to supplyinformation needed to calibrate and/or otherwise control the device.

In one aspect, the first component provides the necessary elements todrive the extraction and sensing of the analyte. The sensing electronicsthen communicate the results (data) of extraction and sensing to thesecond component (user interface) where microprocessing functionsprocess the data and/or display such data to the user. Algorithms(programs) capable of data manipulation are known to those of skill inthe art. Suitable algorithms useful in processing data (e.g., predictingphysiological values, signal processing, predicting concentration, andthe like) are described, for example, in International Publication WO99/58973, published 18 Nov. 1999 and International Publication WO99/58050, published Nov. 18, 1999. In addition, co-pending, co-ownedU.S. Ser. No. 09/198,039, filed 30 Sep. 1998, describes how a Mixturesof Experts algorithm can be used predict a concentration of an analyteof interest. Further, it will be apparent that in alternativeembodiments, one or more functions of the microprocessor (e.g., datamanipulation, calibration, etc.) can be located within the secondcomponent.

In another aspect, one or more of the sampling and sensing functions ofthe first component are controlled by the second component. For examplethe operation of the sampling device can be controlled by a controller(e.g., a microprocessor with one or more components located in thesecond component of the monitoring system), which is in operablecommunication with the sampling electrodes, the sensor electrodes, thepower supply, as well as optional temperature and/or conductance sensingelements, a display, and other electronics.

The user interface (second component) may take a variety ofconfigurations, for example, a credit card like device (e.g.,“smartcard”), a watch, pager, or cell phone device that includes memory,a display such as a liquid crystal display (LCD) and buttons. Thebuttons can be used to control what is displayed and record eventsoccurring during use of the product (e.g., meals, exercise, insulindoses). The user interface may also be a remote device such as apersonal computer or network.

Turning now to the specific embodiments shown in the Figures, FIG. 1Ashows one embodiment of the present invention in which the firstcomponent is worn on the torso (next to the skin) and the user interfaceis worn as a watch. In this embodiment, the first component(sampling/sensing) relays data about the analyte of interest to thesecond component (user interface) which then displays the data. In thisembodiment, the first component includes microprocessing functions thatcontrol sampling and sensing and, in addition, can include dataprocessing functions. The data obtained (and/or processed) by the firstcomponent is then transmitted via wireless communication (see Section IVbelow) to the user interface for display.

FIG. 1B shows an embodiment similar to that of FIG. 1A where the firstcomponent is worn on the torso and the second component takes the formof a watch. In this embodiment, the first component relays informationabout the analyte to the second component, which containsmicroprocessing functions (e.g., data processing) and displaycapabilities.

FIG. 1C depicts yet another embodiment where the first component is wornon the torso and the second component is worn as a pager-like device,shown on the belt of the user in FIG. 1C. The second component includesbuttons and display panel. Further, the first and second components arein two-way communication with one another. Because of two-waycommunication, the user has the ability to control the first componentwith the second component, for example, using the buttons to controlcollection and sensing intervals and/or data manipulation. The firstcomponent will also generally include microprocessing function, forexample to control sampling and sensing functions, collect and/or relaydata to the second component.

FIG. 1D depicts an embodiment of the present invention in which thefirst component includes virtually all the microprocessing functions(e.g., control of sampling/sensing, data manipulation, calibration,etc.). The first component is worn next to the skin, for example, underthe clothing on the torso. As shown in FIG. 1D, the first componentincludes a display panel and buttons (e.g., for controlling themicroprocessor and/or display). In this embodiment, the first componentrelays data to the second component for display. The second component isdepicted as a watch-like structure and includes a display panel, buttons(e.g., for determining what data is displayed and how it is displayed),and electronics controlling the display.

FIG. 1E depicts yet another embodiment where the first and secondcomponents are in two-way communication with one another. The firstcomponent is pictured as being worn by the user on the arm and thesecond component is depicted as a pager-like device on the belt. Thesecond component includes a display panel and buttons. Because thecomponents are in two-way communication, microprocessing functions canbe divided between these components in any number of ways. For example,the second component can control the sampling/sensing of the firstcomponent (e.g., collection intervals, calibration, etc), receiveanalyte data from the first component, manipulate and display theanalyte data. Further, buttons allow for the user to interface with themonitoring system, for example to control one or more of these aspects.Alternatively, the first component can contain the control functions forsampling/sensing and, optionally, calibration and/or data manipulation.This data can then be transmitted to the second component for furthermanipulations, if necessary, and display.

FIG. 1F shows an embodiment of the present invention depicting the twoway wireless communication between the first component (labeled “sensor”in the Figure) and the second component (depicted as a watch in theFigure). The user interface includes buttons, microcontroller functionsand, in addition, is capable of displaying time, date and analyte datato the user. The sensor will typically be placed next to the skin andthe watch worn around the wrist of the user.

FIG. 1G shows another embodiment having bi-directional wirelesscommunication between the sensor (first component) and user interface(second component), depicted in the Figure as a pager-type device.Similar to the embodiment shown in FIG. 1F, the user interface (e.g.,pager-type device) includes buttons, microcontroller functions and, inaddition, is capable of visually displaying time, date and analyte datato the user. In some embodiments, the pager-type device will also becapable of sending auditory and/or tactile (e.g., vibrational) signalsto the user regarding analyte data, time, etc. The sensor component istypically be placed next to the skin of the user and the pager-typedevice worn outside the clothes or carried in a purse, bag, briefcase orthe like.

FIG. 1H shows another embodiment having bi-directional wirelesscommunication between the sensor (first component) and user interface(second component), depicted in the Figure as a credit card-type device.Similar to the embodiment shown in FIGS. 1F and 1G, the user interface(e.g., credit card) includes buttons, microcontroller functions and, inaddition, is capable of visually displaying time, date and analyte datato the user. Further, the user interface can also be designed to includeother information about the user. In some embodiments, the credit carddevice will also be capable of sending auditory and/or tactile (e.g.,vibrational) signals to the user regarding analyte data, time, etc. Thesensor component is typically be placed next to the skin of the user andthe credit card device worn outside in the pocket or carried in thewallet of the user.

IV. Communication Between Components

The at least two components of the present invention are preferably inoperative communication with one another. The operative communicationcan include, for example, the following: one-way communication from thebiosensor (e.g., the first component) to the user interface (e.g., asecond component), or two-way communications between the first componentand the second component. Communication with third or more componentswith either first or second component can be one-way or two-waydepending on the particular type of information being communicated.Preferably, the at least two components of the monitoring system havetwo-way communications. Furthermore, any of the communication means(devices) described herein can be used to maintain operativecommunication between the at least two components and any otheradditional components (e.g., alarm, remote modem or PC, display, ordelivery unit).

Mechanism for providing operative communication between the twocomponents include, but are not limited to, the following:

1) One-way communication from the sensing mechanism (first component) tothe display electronics (second component). The second component caninclude mechanism for data storage, user inputs, and the ability toupload information to a host computer.

2) Similar to (1), but with data storage, user inputs, and upload tohost computer from the first component.

3) Two-way communications (send and receive) between the first andsecond components, where data storage, user inputs, and upload to hostcomputer can either (a) all be in either the first or second component,or (b) split in any combination between the two sets of electronics(i.e., the first and second components).

4) (1), (2), or (3) with wireless communications link between the twocomponents.

5) (4) with wired or wireless communications to a host device for dataupload or automatic reporting to healthcare provider via telephone,internet, or wireless communications. For example, a bedside receiverthat automatically reports to a patient's personal physician. This samebedside device could also function as a telephone.

6) (4) with any of the following wireless communications technologies(for example, short range communication, i.e., less than or equal to 3meters, or longer range), including but not limited to:

Electromagnetic waves, including but not limited to, low frequencyelectromagnetic waves (frequency range about 1 Hz–1 Mega Hz); mediumfrequency electromagnetic waves (frequency range about 1 Mega Hz–500Mega Hz); and high frequency electromagnetic waves (frequency rangeabout 500 Mega Hz–20 Giga Hz). Further, it is to be understood that suchranges for electromagnetic waves are approximate and may be subdividedinto further categories, for example, by the FCC, which indicates thatlow frequency (LF) ranges between about 30 kHz and about 300 kHz; mediumfrequency (MF) ranges between about 300 kHz and about 3 Mega Hz (MHz);high frequency (HF) ranges between about 3 MHz and about 30 MHz; veryhigh frequency (VHF) ranges between about 30 MHz and about 300 MHz;ultra high frequency (UHF) ranges between about 300 MHz and 3 Giga Hz(GHz); super high frequency (SHF) ranges between about 3 GHz and about30 GHz; and extra high frequency (EHF) ranges between about 30 GHz andabout 300 GHz.

Capacitance coupling between, for example, a subject's body and theenvironment/air (frequency range about 1 Hz–1 Mega Hz);

Inductive coupling (i.e., time varying magnetic field; not freelypropagating electromagnetic wave);

Close coupled inductive (i.e., inductive but so weak that it works onlyat very short range). This would likely require bringing the twocomponents (e.g., a display device and sensor electronics) in closeproximity whenever the data needs to be displayed;

Brief electrical contact whenever data is needed at the display;

Infrared coupling (using infrared light, e.g., as in low speedcommunications links to computers and personal digital assistants), and

High frequency acoustic energy.

7) (5) with any of the links mentioned in (6).

8) combinations and modifications of (1)–(7), above.

Preferably, the communication between the at least two components is awireless link. Wireless links allow for the uploading of data from themonitoring system to a personal computer or personal digital assistant(having the necessary receiver electronics) for viewing by the user,family member, medical care team or researchers. Although wire-likelinks can also be used for this purpose, wireless links are preferred toenhance user convenience.

A variety of approaches are available for such wireless communicationincluding, but not limited to, electromagnetic waves such as radiofrequency with carrier bands from 20 kilo Hertz to 20 Giga Hertz (see,e.g., Freiherr (1998) Medical Device and Diagnostic Industry,August:83–93); capacitance coupling; inductive coupling, infraredcoupling, high frequency acoustic energy and frequency hopping schemes.

In one aspect, wireless communications are provided by electromagneticwaves (radio-frequency). The selection of which carrier frequency can bereadily determined by one of skill in the art in view of range (e.g.,distance between sensing mechanism and user interface), blocking by thehuman body and clothes, power consumption, bandwidth, noisesusceptibility, antenna size, FCC regulations, selected communicationprotocol, cost and availability of starting materials. Two-way pagingelectronics and networks, for example RF (radio-frequency) transceivers,also find use in the present invention, for example technologymanufactured and commercially available from High Desert RDN, Rupert,Id.; RF Monolithics, Inc., Dallas, Tex.; and Motorola, Inc. Inparticular, the miniature, spread spectrum transceiver known as theRF-SOI sensor transceiver™ (High Desert RDN, Rupert, Id.) requires lessthan 0.5 volts of electrical power while providing a sensor or analysishost device the ability to gather and transceive data in real time.Short-range wireless data communications are also commerciallyavailable, for example, the wireless data transceiver systems designedand available from RF Monolithics, Inc., Dallas, Tex. Two-way pagingdevices, e.g., ReFlex® paging hardware and service (Motorola, Inc.) arealso available. These technologies can be used to transmit the data fromthe monitoring system to a file server (for example, a file server thatis part of a wide area network (WAN) such as the internet). Theinformation on the file server can then be readily accessed usingstandard web browsing software with appropriate security featuresimplemented for confidentiality. In addition, cellular and/or cordlesstelephone networks can be used to transfer the data to a file server foraccess. See, e.g., U.S. Pat. Nos. 5,838,730 and 5,574,775. Wirelesscommunications for local area networks (LAN) are described, for example,in U.S. Pat. Nos. 5,875,186 and 5,987,033. U.S. Pat. No. 5,077,753 andwww.bluetooth.com for descriptions of Bluetooth technology, a wirelesscommunication technology for data and voice.

In another embodiment, the wireless link (e.g., communication mechanism)is established by capacitance coupling, for example using a technologycalled Personal Area Network (PAN; WO 96/36134, N. Gershenfeld, et al.,published 14 Nov. 1996). This technology is an example of capacitancecoupling involving the use of the human body to carry current, and thusinformation, from one device to another. These devices have to be eitherin direct contact, or in close proximity, to the body. A low frequencycarrier, e.g., below 1 MHz, is used to transmit the information.Advantages of PAN include that it may require less energy for datatransmission, the potential of better control over security oftransmitted information, and the use of simple low cost electronics.

As noted above, inductive coupling can also be used to establishwireless communication abilities between the two components of themonitoring system described herein. Inductive coupling usually requiresthat the communicating components be in relatively close physicalproximity to each other. Suitable inductive coupling technology isdescribed, for example, in U.S. Pat. No. 5,882,300 to Malinouskas,issued Mar. 16, 1999 directed to a wireless patient monitoring apparatusthat employs inductive coupling. Wireless systems that make use ofinfrared coupling are also known and described, for example in U.S. Pat.Nos. 5,103,108 and 5,027,834, as are wireless communication systems thatmake use of high frequency acoustic energy (e.g., ultrasound).Ultrasonic wireless communications typically use frequencies betweenabout 100 KHz and 1.0 MHz (see, e.g., U.S. Pat. No. 5,982,297).

V. Additional Components

The present invention may also include, in addition to the first andsecond components, other additional components, for example, additionaldisplay units, alarm mechanisms and/or delivery units such as pumps.Alarm mechanisms could be used to warn the user when the concentrationof the analyte gets above or below a pre-set threshold value. In certainembodiments, the alarm will be remote from (and in communication with)the first and second components, while in other embodiments, the alarmcan be included within the structure of the first or second components.

In certain embodiments, a component comprising a delivery unit capableof delivering a substance (e.g., therapeutic substance) to the subjectis included in the present invention. The substance delivered to thesubject will of course depend on the analyte being monitored. Forinstance, in the case where glucose is the analyte, the delivery unitwill preferably deliver insulin. Thus, in certain embodiments, after thesampling/sensing mechanism determines the concentration of the analyteof interest, this information can be relayed to the delivery unit.Microprocessing functions within the delivery unit can then determinethe appropriate amount of therapeutic substance to be delivered to thesubject. Alternatively, it will be apparent that the determination ofthe amount of therapeutic substance to be delivered by the delivery unitcan be made by any of the components of the system, for example by thefirst or second components following appropriate data collection andanalysis. Thus, in certain embodiments, the delivery unit can beautomatically controlled by the first and/or second components of themonitoring system. In addition, in some embodiments, the user can haveinput as to the amount of substance delivered by the delivery unit. Forexample, after reviewing the display of data obtained from thesampling/sensing component, the user can determine the amount ofsubstance to be delivered and transmit appropriate instructions (e.g.,via programming the microprocessing functions of the user interface) tothe delivery unit. Suitable delivery units, for example, insulin pumpsare described in the art. See, e.g., U.S. Pat. Nos. 5,112,614;5,995,860; and 5,062,841. Implantable glucose monitoring-telemetrydevices have also been described, see, e.g., U.S. Pat. No. 4,703,756;Atanasov et al. (1997) Biosensors & Bioelectronics 12:669–679; Black etal. (1996) Sensors and Actuators B31:147–153; McKean and Gough (1988)IEEE Transactions on Biomedical Engineering 35:526–532. The deliveryunit may be implantable or external to the subject.

Further, it is to be understood that the present invention includesembodiments having one or more additional components (e.g., both alarmand delivery unit). It will also be apparent that the additionalcomponent(s) are preferably in operably communication with at least oneof the first and second components. The nature of the communicationbetween the additional component(s) and the first and/or secondcomponents can be readily determined by a skilled artisan using thecommunications mechanisms and factors described herein, for example,whether the additional component a separate structure, whether it isimplanted or external, the nature of the microprocessor(s) in thecomponents and the like. Preferably, the communication between theadditional(s) components is wireless.

Exemplary embodiments of a monitoring system having three components areshown in FIGS. 1I to IL. FIG. 1I depicts an embodiment of the presentinvention which includes three separate components: a sampling/sensingmechanism (“sensor”); a user interface (depicted as a credit card) and adrug delivery unit (“insulin pump”). As depicted in the Figure, allthree components have bi-directional wireless communication abilitieswith each of the other elements. This allows, for example, for afeedback loop to be established between the sensor and the insulin pumpwithout input from the user. The sensor component samples and senses theanalyte (e.g., glucose) and microcontroller functions in either theinsulin pump or the sensor analyze and translate the data into theamount of insulin required to be administered to the user. Further, thebi-directional wireless communication abilities also allow forsituations in which the user controls the amount of insulin infused bythe pump, for example, taking into account meals, exercise or otherfactors. As described above, the credit card can include a variety offunctions (e.g., date, time, analyte data, other information) and canemploy a variety of display mechanisms (e.g., visual, auditory ortactile). The sensor is preferably worn next to the skin while thecredit card can be carried in a pocket or wallet. The insulin pump ispreferably at least partially implanted (e.g., subcutaneously) in theuser.

FIG. 1J depicts an embodiment similar to that of FIG. 1I except that theuser interface is depicted as a watch rather than a credit card.Similarly, FIG. 1K depicts a three component, bi-directional wirelesscommunication system as described for FIG. 1I, except that the userinterface is a pager-type device.

FIG. 1L depicts an embodiment of the present invention which includesthree separate components: a sampling/sensing mechanism (“sensor”); auser interface (depicted as a watch) and a remote modem. As depicted inthe Figure, the modem receives information from the sensor and userinterface. It is to be understood that, in some embodiments, the userinterface and sensor will also be in communication with one another. Thepresence of a remove modem allows the sharing of data between the userand variety of other interested parties. For example, the modem can belinked to a wide area network (WAN) such as the internet and transmittedto secure file server for accessed using, for example, web browsingsoftware (with appropriate security measures) by a doctor or hospitalpersonnel. As described above, the watch can include a variety offunctions (e.g., date, time, analyte data, other information) and canemploy a variety of display mechanisms (e.g., visual, auditory ortactile). The sensor is preferably worn next to the skin while the watchis worn on the wrist.

Although preferred embodiments of the subject invention have beendescribed in some detail, it is understood that obvious variations canbe made without departing from the spirit and the scope of the inventionas defined by the appended claims.

1. A monitoring system for frequently measuring an analyte present in asubject and providing to said subject self-monitoring of said analyte,said monitoring system comprising: (A) a first component to be placed incontact with a skin or mucosal surface of said subject comprising (i) asampling mechanism for transdermally extracting the analyte from thesubject, wherein said sampling mechanism is adapted for extracting theanalyte across a skin or mucosal surface of said subject; (ii) a sensingmechanism in operative contact with the analyte extracted by thesampling mechanism, wherein said sensing mechanism obtains a signal fromthe extracted analyte and said signal is specifically related to anamount or concentration of analyte; and (iii) a first mechanism forproviding operative communication with a second component of themonitoring system, wherein (a) said operative communication compriseswireless communication technology employing electromagnetic waves, and(b) said first and second components are separately housed; and (B) thesecond component comprising (i) a user interface; (ii) a secondmechanism for providing operative communication with the firstcomponent, wherein (a) said operative communication comprises wirelesscommunication technology employing electromagnetic waves, (b) the secondcomponent receives the signal from the first component, and (c) iscapable of communicating with a third component remote from the subjectbeing monitored without communicating with the first component; (iii) acomputing mechanism that converts the signal from the extracted analyteto an output indicative of the amount or concentration of analyteextracted by the sampling mechanism; (iv) a visual display said outputto the subject; (v) an alarm that produces tactile and/or auditorysignals to warn the subject when the amount or concentration of analyteis above a pre-set threshold value or below a pre-set threshold value;and (vi) the second component configured to be worn by the subject on awrist of the subject or a belt of the subject, or configured to becarried by the subject as a credit-card-type unit or a pager-type unit.2. The monitoring system of claim 1, wherein the wireless communicationtechnology employs low frequency electromagnetic waves in a frequencyrange of about 1 Hz. to about 1 Mega Hz.
 3. The monitoring system ofclaim 1, wherein the wireless communication technology employs mediumfrequency electromagnetic waves in a frequency range of about 1 Mega Hz.to about 500 Mega Hz.
 4. The monitoring system of claim 1, wherein thewireless communication technology employs high frequency electromagneticwaves in a frequency range of about 500 Mega Hz. to about 5 Giga Hz. 5.The monitoring system of claim 1, wherein the wireless communicationtechnology employs capacitance coupling between the subject andsubject's environment.
 6. The monitoring system of claim 1, wherein thewireless communication technology employs inductive coupling.
 7. Themonitoring system of claim 1, wherein the wireless communicationtechnology employs infrared coupling.
 8. The monitoring system of claim1, wherein the second component relays command signals to the firstcomponent.
 9. The monitoring system of claim 8, wherein the commandsignals include signals to control operation of the sensing mechanism.10. The monitoring system of claim 8, wherein the command signalsinclude signals to control operation of the sampling mechanism.
 11. Themonitoring system of claim 1, wherein the second component is capable ofstoring analyte-related data.
 12. The monitoring system of claim 1,wherein the analyte comprises glucose.
 13. The monitoring system ofclaim 1, wherein said subject is a mammal.
 14. The monitoring system ofclaim 13, wherein said mammal is a human.
 15. The monitoring system ofclaim 1, further comprising (C) a delivery device component comprising(i) a delivery device; and (ii) a third mechanism for providingoperative communication with the first and second components, whereinthe communication between first and second components and the thirdcomponent is wireless.
 16. The monitoring system of claim 15, whereinthe delivery device is adapted to be implanted in the subject.
 17. Themonitoring system of claim 15, wherein the delivery device is adapted tobe external to the subject.
 18. The monitoring system of claim 15,wherein the delivery device comprises an insulin pump.
 19. Themonitoring system of claim 1, wherein (C) the third component comprises(i) a modem or personal computer; and (ii) a third mechanism forproviding operative communication with the first and second components,wherein said operative communication comprises wireless communicationtechnology that employs electromagnetic waves.
 20. The monitoring systemof claim 19, wherein the analyte comprises glucose.
 21. The monitoringsystem of claim 19, wherein the modem or personal computer is operablylinked to a wide area network (WAN).
 22. The monitoring system of claim1 wherein the second component includes buttons for controlling, by thesubject, data sampling intervals of the first component and buttons forcontrolling, by the subject, data manipulation and display in the secondcomponent.
 23. A method for self-monitoring of analyte present in asubject, the method comprising the steps of: (a) placing a firstcomponent in contact with a skin or mucosal surface of the subject; (b)transdermally extracting analyte from the skin or mucosal surface of thesubject, by the first component; (c) obtaining a signal, by the firstcomponent, specifically related to an amount or concentration of theanalyte; (d) providing the subject a second component adapted to be wornor carried; (e) wirelessly communicating, using electromagnetic waves,between the first component and the second component; (f) receiving, bythe second component, the signal obtained in step (c) from the firstcomponent; (g) computing, by the second component, the amount orconcentration of the analyte extracted by the first component; (h)visually displaying to the subject a warning, by the second component,if the amount or concentration of analyte is above or below a pre-setthreshold value; and (i) audibly alarming the subject, by the secondcomponent, if the amount or concentration of analyte is above or below apre-set threshold value.
 24. The method of claim 23 including thefollowing step: controlling, by the subject, data sampling intervals ofthe first component and data manipulation and display of the secondcomponent.
 25. The method of claim 23 including the step of: wirelesslytransmitting by the second component to a remote third component theamount or concentration of analyte computed by the second component.